Inversion of the Warburg Effect: Unraveling the Metabolic Nexus between Obesity and Cancer

Abstract

Obesity is a well-established risk factor for cancer, significantly impacting both cancer incidence and mortality. However, the intricate molecular mechanisms connecting adipose tissue to cancer cell metabolism are not fully understood. This Review explores the historical context of tumor energy metabolism research, tracing its origins to Otto Warburg's pioneering work in 1920. Warburg's discovery of the "Warburg effect", wherein cancer cells prefer anaerobic glycolysis even in the presence of oxygen, laid the foundation for understanding cancer metabolism. Building upon this foundation, the "reverse Warburg effect" emerged in 2009, elucidating the role of aerobic glycolysis in cancer-associated fibroblasts (CAFs) and its contribution to lactate accumulation in the tumor microenvironment, subsequently serving as a metabolic substrate for cancer cells. In contrast, within high-adiposity contexts, cancer cells exhibit a unique metabolic shift termed the "inversion of the Warburg effect". This phenomenon, distinct from the stromal-dependent reverse Warburg effect, relies on increased nutrient abundance in obesity environments, leading to the generation of glucose from lactate as a metabolic substrate. This Review underscores the heightened tumor proliferation and aggressiveness associated with obesity, introducing the "inversion of the Warburg effect" as a novel mechanism rooted in the altered metabolic landscape within an obese milieu. The insights presented here open promising avenues for therapeutic exploration, offering fresh perspectives and opportunities for the development of innovative cancer treatment strategies.

Figure 1

Hypothesized mechanisms that connect obesity to cancer. The accumulation of excess fat in white adipocytes compromises their normal function, ultimately leading to apoptosis, or cell death, triggered by factors like hypoxia and increased extracellular matrix stiffness. During this apoptotic phase, cellular contents are released from dying adipocytes. These released contents, including free fatty acids, initiate receptor-mediated activation of Toll-like receptor 4 (TLR4) in resident macrophages. TLR4 activation prompts the secretion of pro-inflammatory cytokines, chemokines, and growth factors by these macrophages through the activation of the nuclear factor-kappa B (NF-κB) pathway. Subsequently, there is an intensified intracellular signaling cascade in macrophages involving NF-κB, STAT3, and JNK-related pathways, resulting in the sustained release of pro-inflammatory cytokines, thereby creating a state of chronic inflammation. The heightened secretion of pro-inflammatory cytokines and hormones by white adipocytes due to obesity further enhances the metastatic potential of cancer cells. Additionally, the obesity-related increased release of pro-inflammatory cytokines amplifies the expression of aromatase in white adipocytes. This enzyme is responsible for converting androgens into estrogens within adipose tissues, which, in turn, promotes the initiation and growth of mammary tumors by stimulating the proliferation of cancer cells. Moreover, adipocyte-released free fatty acids in cases of obesity direct cancer cells toward β-oxidation as an energy source, providing the necessary fuel for sustaining the progression of cancer.

Figure 2

Schematic diagram depicting the distinctions among oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis (including the Warburg effect). In the presence of oxygen, non-proliferating (differentiated) tissues primarily utilize glucose through glycolysis, converting it into pyruvate, and subsequently, most of that pyruvate is thoroughly oxidized in the mitochondria to produce CO₂ via the process known as oxidative phosphorylation. This metabolic pathway relies on oxygen as the ultimate electron acceptor, making oxygen an essential component. However, when oxygen levels are low, cells have a backup plan. They can reroute the pyruvate generated by glycolysis away from the mitochondria, leading to the production of lactate (anaerobic glycolysis). This allows glycolysis to continue by recycling NADH back into NAD⁺ but results in much less ATP production compared to oxidative phosphorylation. Dr. Warburg observed that cancer cells tend to convert most of the glucose into lactate, regardless of oxygen availability (aerobic glycolysis). Interestingly, this behavior is also seen in normal rapidly dividing cells. While both cancer cells and rapidly dividing normal cells still have functional mitochondria and some oxidative phosphorylation activity, aerobic glycolysis is less efficient than oxidative phosphorylation at generating ATP.

Figure 3

Reverse Warburg effect. In the concept of the reverse Warburg effect, different groups of cancer cells can exchange and utilize substances among themselves. More specifically, cancer cells that predominantly rely on oxidative processes can absorb lactate produced by hypoxic cancer cells engaged in aerobic glycolysis to power their oxidative phosphorylation (OXPHOS). On the other hand, hypoxic cancer cells can also take in reactive oxygen species (ROS) produced by oxidative cancer cells. This uptake triggers the activation of hypoxia-inducible factor 1α (HIF-1α) and promotes aerobic glycolysis. This provides cancer cells with an additional mechanism that boosts their ability to proliferate and survive.

Figure 4

Mechanisms underlying hyperglycemia-promoted cancer progression. Elevated blood sugar levels (hyperglycemia) bring about specific metabolic changes within cancer cells, influencing their cellular functions. Abbreviations: GLUT1, glucose transporter 1; PPP, pentose phosphate pathway; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HIF, hypoxia-inducible factor-1; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; TCA, tricarboxylic acid cycle.

Figure 5

Representative model of the central energetic metabolism of cancer cells under different nutritive statuses in which, under an obesity microenvironment, the Warburg effects invert with lowering lactate and de novo synthesis of glucose. Increased pyruvate in adiposity benefits from the contribution not only from lactate but also from amino acid catabolism. The cancer Krebs cycle under adiposity is fed from lipid and amino acid catabolism, in particular lipolysis and beta-oxidation, but also from deamination of glutamine (glutaminolysis).